Association between the AKT1 single nucleotide polymorphism (rs2498786, rs2494752 and rs5811155) and microscopic polyangiitis risk in a Chinese population.

Microscopic polyangiitis (MPA) is an autoimmune disease, characterized by ANCA in blood and necrotizing inflammation of small and medium-sized vessels, one of the three clinical phenotypes of ANCA-associated vasculitis (AAV). Autophagy has been confirmed to be involved in the pathogenesis of AAV. AKT1 is one of the autophagy-regulated proteins. Its single nucleotide polymorphisms (SNPs) are associated with multiple immune-related diseases, but there are rarely studies in AAV. The incidence rate of AAV has a notable geographic difference, and MPA is predominant in China. The aim of this study was to investigate the association between AKT1 SNP and MPA risk. Genotypes of 8 loci in AKT1 were evaluated by multiplex polymerase chain reaction (PCR) and high-throughput sequencing in 416 people, including 208 MPA patients and 208 healthy volunteers from Guangxi in China. Additionally, data of 387 healthy volunteers from China were obtained from the 1000Genomes Project on public database. Differences were observed between the loci (rs2498786, rs2494752, and rs5811155) genotypes in AKT1 and MPA risk (P = 7.0 × 10-4, P = 3.0 × 10-4, and P = 5.9 × 10-5, respectively). A negative association was detected in the Dominant model (P = 1.2 × 10-3, P = 2.0 × 10-4 and P = 3.6 × 10-5, respectively). A haplotype (G-G-T) was associated with MPA risk negatively (P = 7.0 × 10-4). This study suggests that alleles (rs2498786 G, rs2494752 G and rs5811155 insT) are protective factors for MPA and alleles (rs2494752 G and rs5811155 insT) for MPO-ANCA in patients with MPA. There is a haplotype (G-G-T), which is a protective factor for MPA. It suggests that the role of AKT1 in MPA/AAV needs further study to provide more intervention targets for MPA/AAV.

Differential Expression of Toll-Like Receptor Signaling Pathway Is Associated with Microscopic Polyangiitis in Peripheral Blood Neutrophils.

Constitutive or excessive activation of Toll-like receptor (TLR) signaling pathway can disrupt the body's immune tolerance to autoantigen, thus promoting the development of autoimmune disease. However, the expression profile of TLR signaling pathway in peripheral blood neutrophils in the pathogenesis of microscopic polyangiitis (MPA) remains unclear. Thus, improved understanding of the pathobiology of this disease may aid in the development of therapeutic targets for patients with MPA. In the present study, we assessed the expression of TLR signaling pathway-related genes in peripheral blood neutrophils in patients with MPA. PCR array analysis was performed on 20 patients with MPA and 12 healthy controls. Gene expression profile was performed using the human TLR for autoimmunity and inflammation PCR array of Genecopoeia, containing 84 genes related to TLR signaling pathway and six house-keeping genes. We then used quantitative real-time PCR to validate the array test. The array results identified 13 upregulated genes and 5 genes which were downregulated. The resulting qRT-PCR was consistent with the findings by PCR array. Our results suggest that peripheral blood neutrophils display changes in the expression of TLR signaling pathway-related genes associated with the pathogenesis of microscopic polyangiitis.

MTOR gene polymorphism may be associated with microscopic polyangiitis susceptibility in a Guangxi population of China.

OBJECTIVE: Microscopic polyangiitis (MPA) onset is affected by genetic predisposition. Autophagy plays a certain role in antineutrophil cytoplasmic antibody-associated vasculitis developing. A key factor in autophagy regulating, the genetic polymorphism of MTOR gene is essential. The objective was to explore the associations between MTOR gene polymorphism and MPA susceptibility in a Guangxi population of China. METHODS: A sum of 208 MPA cases and 209 healthy volunteers from Guangxi in this case-control study, four important single nucleotide polymorphism (SNP) loci of MTOR gene including rs3806317, rs1064261, rs1883965 and rs2295080 were examined. Multiplex polymerase chain reaction combined with high-throughput sequencing was performed. Subgroup analysis was evaluated by gender and ethnicity. Linkage disequilibrium and haplotype analysis were tested. Multi-SNPs interaction among mTOR signaling pathway was assessed. RESULTS: For rs2295080, homozygous mutant GG genotype was associated with a decreased susceptibility of MPA in recessive model (OR = 0.38, 95%CI: 0.14-1.00, p = 0.040), particularly in the subgroup of female (OR = 0.16, 95%CI: 0.03-0.74, p = 0.006) and Han population (OR = 0.32, 95%CI: 0.10-1.00, p = 0.034). Individual carrying G allele was linked with decreasing MPA susceptibility in Han population of Guangxi (OR = 0.65, 95%CI: 0.44-0.97, p = 0.036). In haplotype analysis, the haplotype AAT was correlated with increasing susceptibility of MPA (OR = 1.347, 95%CI: 1.004-1.807, p = 0.046). Moreover, in the multi-SNPs interaction analysis, the six-locus model was identified as the best interaction model (p < 0.05). CONCLUSION: These findings suggest that rs2295080 polymorphism of MTOR gene may be associated with MPA susceptibility in a Guangxi population of China and G allele might be an important protective factor.

LINC00461 facilitates HNSCC development and reduces chemosensitivity by impairing miR-195-mediated inhibition of HOXA10.

Homeobox A10 (HOXA10) has been regarded to serve as an oncogene in head and neck squamous cell carcinoma (HNSCC). This study was intended to explore the interaction among the long intergenic noncoding RNA 00461 (LINC00461), microRNA (miR)-195, and HOXA10, and to investigate its role in epithelial-mesenchymal transition (EMT) and chemoresistance in HNSCC. The effects of LINC00461, miR-195, and HOXA10 on the EMT and chemoresistance of HNSCC cells were analyzed by comprehensive analysis of gain- and loss-of-function techniques. The intimate relationships among LINC00461, miR-195, and HOXA10 were investigated by several procedures such as RNA-binding protein immunoprecipitation, RNA pull-down, and dual-luciferase reporter assays. A xenotransplantation tumor model in nude mice was established for the assessment of the tumorigenic ability of the cells in vivo. Our findings indicated that LINC00461 was highly expressed in HNSCC and its overexpression induced EMT and precipitated the chemoresistance of HNSCC cells to cisplatin. The LINC00461 could bind to miR-195 while miR-195 targeted HOXA10 independently. Moreover, LINC00461 impaired miR-195-mediated inhibition of HOXA10 to induce EMT and increase the chemoresistance in HNSCC. Tumor weight and volume were reduced by lentivirus-mediated elevation of miR-195 by inhibition of HOXA10, which could be annulled by LINC00461 overexpression. LINC00461 downregulates the expression of miR-195 to subsequently upregulate the expression of HOXA10, thereby promoting EMT and enhancing chemoresistance in HNSCC.